PROJECT SUMMARY/ABSTRACT The most aggressive variant of glioma, glioblastoma multiforme (GBM), afflicts approximately 20,000 newly diagnosed patients within the United States annually. Despite maximal surgical and adjuvant chemo- radiotherapeutic intervention, prognosis remains dismal, with median survival being 14.2 months. Clinical progression is invariably due to tumor recurrence within a 2cm margin of the original surgical resection cavity, with recurrent tumors being resistant to additional radiation. Among these radiation resistant recurrent tumor cells, the mesenchymal GBM subtype is predominant. Although primarily studied in the context of metastatic carcinomas, mounting evidence supports a role for cancer epithelial-mesenchymal transition (EMT) related processes in the progression and resistance of GBM to radiotherapy. The primary goal of this work is to provide an EMT-associated clinical target for improving radiation-induced cell death in recurrent glioblastoma cells, thereby increasing overall and progression free survival in this fatal disease that affects men and women globally. To this end, three inter-connected but independent aims are proposed. In Aim 1, the investigator will determine the effects of differential expression of cell-cell adhesion molecules and associated regulators of EMT on radiation induced cell death in patient-derived human glioblastoma cells. The second aim will examine the impact of differential cadherin expression and EMT regulators on the generation of reactive oxygen species (ROS) by external beam radiation treatment (XRT) in GBM. In the final aim, the investigator will evaluate the efficacy of recombinant cadherin-ectodomains and microenvironment modulation on radiation- induced cell death in novel patient-derived human glioblastoma orthotopic xenograft model of recurrent disease.